Project Summary Diabetes is a major risk factor for cardiovascular diseases, and vascular stiffening and calcification are considered the hallmark of diabetes. Therefore there is a major need for engineered vascular grafts with long- term patency and durability to be used in diabetic cardiovascular patients. Tissue-engineered constructs based on collagen and elastin scaffolds and autologous progenitor cells hold great promise to treat vascular diseases, but very little information exists regarding their fate in the diabetic environment. The altered glucose and lipid metabolism characteristic of diabetes results in endothelial dysfunction, accelerated atherosclerosis, activation of inflammation, and fibrosis and impaired healing, all of which are not conducive to the desired integration and remodeling of tissue engineered constructs. The long-term goal of this research is to develop viable tissue-engineered vascular substitutes adapted to withstand diabetes-related complications. The hypotheses, robustly supported by preliminary data, are that both matrix and cells are affected in a diabetic milieu and that treatment of collagen- and elastin-based scaffolds with polyphenols would protect the matrix from stiffening and calcification. To test these hypotheses, adipose derived stem cell-seeded vascular scaffolds will be implanted in type 2 diabetic rats as direct end-to- end anastomoses in the abdominal aorta, and their remodeling and survival will be investigated (Aim 1). To mitigate diabetes-induced alterations, the scaffolds will be treated with polyphenol stabilizing agents prior to cell seeding, and the grafts will be implanted in diabetic rats (Aim 2). Expertise of the PI's scientist mentor, Dr. Vyavahare, PI of this COBRE, and clinical mentor, Dr. Langan, are greatly relevant to the project; core support for stem-cell isolation and characterization and bioimaging of vascular scaffold in animals is essential for this project to succeed. Typically, tissue-engineered constructs and their remodeling are tested in healthy animals for preclinical evaluation. Using a diabetic animal model will provide new information about the molecular mechanisms of this pathology and the fate of collagen- and elastin-based scaffolds in a diabetic environment. Treatment of tissue- derived vascular scaffolds with polyphenols will eventually protect them from diabetic complications and support their future use for cardiovascular tissue engineering in diabetic patients.